The novel structural architecture and cytotoxic nature of the marine alkaloid (-)-Nakadomarin A, render this natural product as an important synthetic target. Isolated from the marine sponge Amphimedon sp. (SS-264) native to the Kerama Islands off the Okinawa coast, (-)-Nakadomarin A is a structurally complex Manzamine-related alkaloid. This natural product is recognized for its novel furan containing 8/5/5/5/15/6 hexacyclic diamine core, a feature previously unobserved in other related alkaloids. (-)-Nakadomarin A exhibits a range of interesting biological activities, most notably its inhibitory activity against the cell growth cycle regulator (CDK4); however, the limited quantities have prohibited further evaluation. This alkaloid may possess other biological properties that have gone undetected, properties which may be of vital importance. Only two laboratories have reported completed syntheses, neither of which is able to access the natural product in quantities relevant to pharmacological studies. An efficient cascade approach to the total synthesis of (-)-Nakadomarin A is proposed. The application of a late-stage transannular Mannich-Pictet-Spengler cyclization should proceed through a cascade event to establish the hexacyclic network of Nakadomarin A. This tandem act is predicted to fuse the hexacyclic framework making up the molecule, while enantioselectively establishing two of the molecule's four stereogenic centers, one of which is a quaternary carbon. The exploration of this annulation strategy and the technologies used within, will presumably define a general means by which to access this structurally related class of alkaloidal natural products. The convergency of this proposed synthesis is expected to provide sufficient quantities of the alkaloid to support critical biological evaluation, an objective which has not yet been successfully achieved to date. PUBLIC HEALTH RELEVANCE: (-)-Nakadomarin A exhibits a range of interesting biological activities; however, the limited quantities have prohibited further evaluation. Chemical synthesis may be the only practical means of providing material for further critical pharmacological testing.